Generation of DNA Aptamers with Functional Activity in Mammalian Cells by Mimicking Retroviruses.

DNA aptamers are single-stranded DNA oligonucleotide sequences that bind to specific targets with high affinity. Currently, DNA aptamers can be produced only by in vitro synthesis. It is difficult for DNA aptamers to have a sustained impact on intracellular protein activity, which limits their clinical application. In this study, we developed a DNA aptamer expression system to generate DNA aptamers with functional activity in mammalian cells by mimicking retroviruses. Using this system, DNA aptamers targeting intracellular Ras (Ra1) and membrane-bound CD71 (XQ2) were successfully generated in cells. In particular, the expressed Ra1 not only specifically bound to the intracellular Ras protein but also inhibited the phosphorylation of downstream ERK1/2 and AKT. Furthermore, by inserting the DNA aptamer expression system for Ra1 into a lentivirus vector, the system can be delivered into cells and stably produce Ra1 over time, resulting in the inhibition of lung cancer cell proliferation. Therefore, our study provides a novel strategy for the intracellular generation of DNA aptamers with functional activity and opens a new avenue for the clinical application of intracellular DNA aptamers in disease treatment.

Nucleic acid aptamer controls mycoplasma infection for inhibiting the malignancy of esophageal squamous cell carcinoma.

Esophageal cancer is one of the most frequent malignant tumors of the digestive tract, among which esophageal squamous cell carcinoma (ESCC) is the main pathological type worldwide. Previous studies have shown microbial infections in the upper digestive tract to be a potential risk factor in ESCC etiology. In this study, we identified that Mycoplasma hyorhinis infection promoted the malignancy of ESCC. In response, we generated a single-stranded DNA aptamer, ZY3A, against M. hyorhinis using the cell-SELEX strategy. The underlying recognition mechanism of ZY3A on M. hyorhinis involves its binding to M. hyorhinis-specific p37 protein. This tool allowed us to provide the first proof-of-concept evidence using a nucleic acid aptamer to control mycoplasma infection. More specifically, we found that ZY3A could neutralize M. hyorhinis infection on ESCC cells by blocking the interaction between p37 protein and its receptor TLR4 on the ESCC cell membrane. As a result, ZY3A inhibited the migration and invasion of M. hyorhinis-infected ESCC cells in vitro and metastasis in vivo. Taken together, these findings indicate that aptamer ZY3A is a potential candidate for development into a novel molecular tool for treatment of M. hyorhinis infection and a safe first-in-class M. hyorhinis-targeting antitumor agent.

Effects of industrial green total factor energy efficiency on haze abatement: A spatial econometric analysis based on China's 272 cities.

Environmental issues represented by haze pollution have become the focus of all sectors of society. Industrial activities, especially industrial energy consumption play an important role in it. After the energy consumption of provincial industrial sectors is decomposed into urban industrial sectors through nighttime light data, this study measures the industrial green total factor energy efficiency (IGTFEE) of Chinese cities from 2003 to 2017, and the haze abatement effect of IGTFEE is investigated from the perspective of spatial correlation. The results show that China's haze pollution and IGTFEE present a positive spatial cluster. Additionally, China's haze pollution has obvious path dependence that shows a monotonous decreasing trend as the aggravation of haze pollution. Meanwhile, although haze pollution shows a serious leakage effect, it plays a warning role in haze control in surrounding areas. This effect is stronger in the most severely polluted areas that have higher economic levels. Not only does the improvement of IGTFEE have a positive effect on local haze abatement but can control haze pollution in spatially related areas through spillover effects and spatial feedback effects. However, the effects are significantly heterogeneous and asymmetric across quantiles, where IGTFEE has a marginal diminishing distribution on haze abatement at the middle and low quantiles, but the haze pollution has intensified at the high quantiles due to the energy rebound effect. The results also reveal that haze abatement conforms to the spatial EKC hypothesis in China. Meanwhile, industrial agglomeration, environmental regulations, and industrial upgrading are vital drivers for haze abatement.

Is the sky of smart city bluer? Evidence from satellite monitoring data.

How to win the "Blue Sky Protection Campaign" is becoming the focus all over the world, especially in developing economies, while the implementation of the smart cities initiative (SCI) is seen to be a feasible program to address the negative environmental externalities through Information and Communication Technologies (ICTs), but it lacks the quantitative evidence so far. This study aims to examine the impacts and potential mechanisms of SCI on air pollution governance from the objective satellite monitoring data within a quasi-natural experiment framework. We find that SCI directly reduces the air pollutants concentration such as PM2.5, SO2, NO2, and smog in urban China and improves the air quality very well, which also has significant and positive spillovers on air pollution governance in adjacent cities. This encouraging phenomenon can also be achieved through contributing to green technological innovation, industrial structure upgrading, and decentralizing urban spatial structure, such that most of can be attributed to the technological effect. Heterogeneity analyses demonstrate that the governance effect of air pollution is more obvious in large smart cities, and increases with the expansion of city size. Additionally, the effect performs better in resource-based smart cities and smart cities with stronger financing capacity and air pollution pressure.

Significant optical force enhancements of nanostructure with balanced gain and loss.

In this paper, we theoretically analyze the optical force between a pair of active and passive plasmonic core-shell nanoparticles (NPs). The optical force between the NPs can be either attractive or repulsive near the critical point while the passive dimer provides only attractive force. We reveal that the reversal of attractive or repulsive force is determined by the relative phase of electric dipole (ED) modes, which can be strongly affected by the gain and loss coefficient κ. Compared with the passive dimer with the same size, the active-passive dimer can exhibit a very high repulsive force (about two orders of magnitude) while remaining the same order magnitude attractive force when the value of coefficient is 0.345. Interestingly, we find that the position of the maximum repulsive force occurs near the critical point. We also investigate the influence of variations in geometrical parameters of the dimer and polarization angle on the force. Finally, the numerical results demonstrate that when the dimer is illuminated by a laser beam, the attractive and repulsive forces can also be achieved. The manipulation of optical force can find potential in optical sorting and transport of NPs.

Comparative analysis of kinetics and mechanisms for Pb(II) sorption onto three kinds of microplastics.

Microplastics (MPs), a kind of novel contaminant, have potential to concentrate and transport heavy metals in the aquatic environment. This feature may affect the distribution and bioavailability of heavy metals. In order to determine the sorption behaviors of heavy metals onto the MPs, the sorption kinetics and mechanisms were investigated between the MPs (polyvinylchloride PVC, polyethylene PE, polystyrene PS) and Pb(II). The results suggested that the Pb(II) sorption onto the MPs were pH- and ionic strength-dependent. The sorption processes were best fitted by the pseudo-second-order model, and the rate-limiting steps were the intraparticle diffusion and final equilibrium process. The maximum sorption capacities of PVC, PE and PS were 483.1 µg/g, 416.7 µg/g and 128.5 µg/g under the condition of 0.01 M NaCl, pH 6.0, T = 298 K. The sorption rate constants were in the following order: PVC

Curcumol and FTY720 synergistically induce apoptosis and differentiation in chronic myelomonocytic leukemia via multiple signaling pathways.

Chronic myelomonocytic leukemia (CML) is a myeloid tumor characterized by MDS (myelodysplastic syndrome) and MPN (myeloproliferative neoplasms). Allogeneic hematopoietic stem cell transplantation, chemotherapy, interferon, and targeted therapy are the main treatment methods for CML. Tyrosine kinase inhibitors (TKIs) are also a treatment option, and patients are currently recommended to take these drugs throughout their lives to prevent CML recurrence. Therefore, there is a need to investigate and identify other potential chemotherapy drugs. Currently, research on CML treatment with a single drug has shown little progress. Fingolimod (FTY720), an FDA-approved drug used to treat relapsing multiple sclerosis, has also shown great potential in the treatment of lymphocytic leukemia. In our study, we find that FTY720 and curcumol have a significant inhibitory effect on K562 cells, K562/ADR cells, and CD34+ cells from CML patients. RNAseq data analysis shows that regulation of apoptosis and differentiation pathways are key pathways in this process. Besides, BCR/ABL-Jak2/STAT3 signaling, PI3K/Akt-Jnk signaling, and activation of BH3-only genes are involved in CML inhibition. In a K562 xenograft mouse model, therapy with curcumol and FTY720 led to significant inhibition of tumor growth and induction of apoptosis. To summarize, curcumol and FTY720 synergistically inhibit proliferation involved in differentiation and induce apoptosis in CML cells. Therefore, synergistic treatment with two drugs could be the next choice of treatment for CML.

Self-Supervised Point Set Local Descriptors for Point Cloud Registration.

Descriptors play an important role in point cloud registration. The current state-of-the-art resorts to the high regression capability of deep learning. However, recent deep learning-based descriptors require different levels of annotation and selection of patches, which make the model hard to migrate to new scenarios. In this work, we learn local registration descriptors for point clouds in a self-supervised manner. In each iteration of the training, the input of the network is merely one unlabeled point cloud. Thus, the whole training requires no manual annotation and manual selection of patches. In addition, we propose to involve keypoint sampling into the pipeline, which further improves the performance of our model. Our experiments demonstrate the capability of our self-supervised local descriptor to achieve even better performance than the supervised model, while being easier to train and requiring no data labeling.

Color-dependent unidirectional scattering of a plasmonic heterodimer investigated by a dipole-dipole interference model.

In this paper, we employ an interference model of two separated electric dipoles to study the color-dependent unidirectional scattering of a plasmonic heterodimer consisting of a pair of gold and silver disks of the same size. The dipole moments in such a dipole-dipole interference model are numerically obtained by a multipole decomposition method. It shows that the power difference between the different scattering directions predicted by the dipole-dipole interference model agrees well with that calculated by the full wave simulation. The dipole-dipole interference model indicates that the scattering directionality of the heterodimer is intimately related to its geometrical parameters, including the height and radius of the disk as well as the distance between two disks. We further show that the color routing of such a heterodimer is also maintained when an electric or magnetic dipole source is positioned in the center of the heterodimer. Finally, we propose an approach to enhance bidirectional scattering by arranging the heterodimer in a line and then the main lobe beamwidth can be reduced to about 26 deg for the right scattering and 29 deg for the left scattering. Our results may be used in designing integrated plasmonic nanocircuits that demand light guiding and routing in nanoscale.

Efficient directional coupling from multilayer-graphene-based long-range SPP waveguide to metal-based hybrid SPP waveguide in mid-infrared range.

Graphene-based and metal-based surface plasmon polariton (SPP) waveguides have attracted intense research interest because they can be used as basic components to propagate electromagnetic (EM) waves in future optical integrated systems. We propose a directional coupler, which can couple EM energy from a multilayer-graphene-based cylindrical long-range SPP waveguide to a metal-based cylindrical hybrid SPP waveguide in the mid-infrared range. This coupler exhibits relatively low coupling length, high coupling efficiency, low insertion loss, and high extinction ratio after adjustment of the wave vector mismatch of the two waveguides. Moreover, this coupler is tolerant to practical fabrication errors like misalignment of graphene layres, and can effectively work in the range of Fermi energy Ef > 0.6 eV when the mobility of graphene varies from 10000 to 800 cm2/Vs. Hence, the coupler offers potential applications in signal routing and information exchange between graphene-based and metal-based SPP waveguides in photonic integrated circuits.

Frequency spacing switchable multiwavelength Brillouin erbium fiber laser utilizing cascaded Brillouin gain fibers.

A new hybrid Brillouin erbium fiber laser scheme that employs cascaded multiple Brillouin gain fibers in a ring cavity to realize multiwavelength laser output with switchable frequency spacing is proposed and experimentally investigated. The multiple frequency downshifting processes introduced by multiple stimulated Brillouin scattering (SBS) effects in one round-trip of the cavity make it possible to realize multiwavelength output with frequency spacing that is an integer multiple of the SBS frequency shifting. With two cascaded SBS fibers, the frequency spacing can be switched between single and double SBS frequency shifting by properly adjusting the Brillouin pump power. Multiwavelength outputs with triple or quadruple SBS frequency spacing are also demonstrated by employing three or four SBS gain fibers, respectively.

Identification and computational annotation of genes differentially expressed in pulp development of Cocos nucifera L. by suppression subtractive hybridization.

BACKGROUND: Coconut (Cocos nucifera L.) is one of the world's most versatile, economically important tropical crops. Little is known about the physiological and molecular basis of coconut pulp (endosperm) development and only a few coconut genes and gene product sequences are available in public databases. This study identified genes that were differentially expressed during development of coconut pulp and functionally annotated these identified genes using bioinformatics analysis. RESULTS: Pulp from three different coconut developmental stages was collected. Four suppression subtractive hybridization (SSH) libraries were constructed (forward and reverse libraries A and B between stages 1 and 2, and C and D between stages 2 and 3), and identified sequences were computationally annotated using Blast2GO software. A total of 1272 clones were obtained for analysis from four SSH libraries with 63% showing similarity to known proteins. Pairwise comparing of stage-specific gene ontology ids from libraries B-D, A-C, B-C and A-D showed that 32 genes were continuously upregulated and seven downregulated; 28 were transiently upregulated and 23 downregulated. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis showed that 1-acyl-sn-glycerol-3-phosphate acyltransferase (LPAAT), phospholipase D, acetyl-CoA carboxylase carboxyltransferase beta subunit, 3-hydroxyisobutyryl-CoA hydrolase-like and pyruvate dehydrogenase E1 ß subunit were associated with fatty acid biosynthesis or metabolism. Triose phosphate isomerase, cellulose synthase and glucan 1,3-ß-glucosidase were related to carbohydrate metabolism, and phosphoenolpyruvate carboxylase was related to both fatty acid and carbohydrate metabolism. Of 737 unigenes, 103 encoded enzymes were involved in fatty acid and carbohydrate biosynthesis and metabolism, and a number of transcription factors and other interesting genes with stage-specific expression were confirmed by real-time PCR, with validation of the SSH results as high as 66.6%. Based on determination of coconut endosperm fatty acids content by gas chromatography-mass spectrometry, a number of candidate genes in fatty acid anabolism were selected for further study. CONCLUSION: Functional annotation of genes differentially expressed in coconut pulp development helped determine the molecular basis of coconut endosperm development. The SSH method identified genes related to fatty acids, carbohydrate and secondary metabolites. The results will be important for understanding gene functions and regulatory networks in coconut fruit.

Multiwavelength fiber laser employing a nonlinear Brillouin optical loop mirror: experimental and numerical studies.

We numerically and experimentally study a multiwavelength fiber laser (MWFL) employing a nonlinear Brillouin optical loop mirror (NBOLM). Taking into account the impact of stimulated Brillouin scattering (SBS) effect on nonlinear polarization evolution, we present the power transmission equation of Stokes lines from the NBOLM. Thereafter, we combine the power transmission equation, coupled wave equations of SBS process in NBOLM, rate and power propagation equations in the erbium-doped fiber (EDF) to build up a model for the MWFL. Using this model, we can explain the impacts of EDF pump power, input polarization state and quarter-wave-plate angle on the number and amplitude flatness of output Stokes lines. Furthermore, the results from numerical calculations are verified by the experimental measurements.

Calycosin-7-glucoside promotes mitochondria-mediated apoptosis in hepatocellular carcinoma by targeting thioredoxin 1 to regulate oxidative stress.

Thioredoxin1 (TRX1) is a key protein that regulates redox and is considered to be a key target for cancer therapy. Flavonoids have been proven to have good antioxidant and anticancer activities. This study aimed to investigate whether the flavonoid calycosin-7-glucoside (CG) exerts an anti-hepatocellular carcinoma (HCC) role by targeting TRX1. Different doses of CG were used to treat HCC cell lines Huh-7 and HepG2 to calculate the IC50. On this basis, the effects of low, medium and high doses of CG on cell viability, apoptosis, oxidative stress and TRX1 expression of HCC cells were investigated in vitro. Also, HepG2 xenograft mice were used to evaluate the role of CG on HCC growth in vivo. The binding mode of CG and TRX1 was explored by molecular docking. Then si-TRX1 was used to further discover the effects of TRX1 on CG inhibition of HCC. Results found that CG dose-dependent decreased the proliferation activity of Huh-7 and HepG2 cells, induced apoptosis, significantly activated oxidative stress and inhibited TRX1 expression. In vivo experiments also showed that CG dose-dependent regulated oxidative stress and TRX1 expression, and promoted the expression of apoptotic proteins to inhibit HCC growth. Molecular docking confirmed that CG had a good binding effect with TRX1. Intervention with TRX1 significantly inhibited the proliferation of HCC cells, promoted apoptosis, and further promoted the effect of CG on the activity of HCC cells. In addition, CG significantly increased ROS production, reduced mitochondrial membrane potential, regulated the expression of Bax, Bcl-2 and cleaved-caspase-3, and activated mitochondria-mediated apoptosis. And si-TRX1 enhanced the effects of CG on mitochondrial function and apoptosis of HCC, suggesting that TRX1 participated in the inhibitory effect of CG on mitochondria-mediated apoptosis of HCC. In conclusion, CG exerts anti-HCC activity by targeting TRX1 to regulate oxidative stress and promote mitochondria-mediated apoptosis.

Selection and identification of a novel ssDNA aptamer targeting human skeletal muscle.

Skeletal muscle disorders have posed great threats to health. Selective delivery of drugs and oligonucleotides to skeletal muscle is challenging. Aptamers can improve targeting efficacy. In this study, for the first time, the human skeletal muscle-specific ssDNA aptamers (HSM01, etc.) were selected and identified with Systematic Evolution of Ligands by Exponential Enrichment (SELEX). The HSM01 ssDNA aptamer preferentially interacted with human skeletal muscle cells in vitro. The in vivo study using tree shrews showed that the HSM01 ssDNA aptamer specifically targeted human skeletal muscle cells. Furthermore, the ability of HSM01 ssDNA aptamer to target skeletal muscle cells was not affected by the formation of a disulfide bond with nanoliposomes in vitro or in vivo, suggesting a potential new approach for targeted drug delivery to skeletal muscles via liposomes. Therefore, this newly identified ssDNA aptamer and nanoliposome modification could be used for the treatment of human skeletal muscle diseases.

Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.

Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1H)-ones were designed rationally, leading to compound 10c with an IC50 of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could work as a novel potential target for the treatment of inflammatory bowel disease (IBD), a disease which is a chronic, relapsing disorder of the gastrointestinal tract inflammation lacking effective treatment. Our results showed that administration of 10c exerted significant anti-IBD effects in the dextran sodium sulfate-induced mice model and alleviated the inflammatory response, indicating that PDE1 could work as a potent target for IBD.

Excitation of Surface Plasmon Polariton Modes with Double-Layer Gratings of Graphene.

A long-range surface plasmon polariton (SPP) waveguide, composed of double-layer graphene, can be pivotal in transferring and handling mid-infrared electromagnetic waves. However, one of the key challenges for this type of waveguide is how to excite the SPP modes through an incident light beam. In this study, our proposed design of a novel grating, consisting of a graphene-based cylindrical long-range SPP waveguide array, successfully addresses this issue using finite-difference time-domain simulations. The results show that two types of symmetric coupling modes (SCMs) are excited through a normal incident light. The transmission characteristics of the two SCMs can be manipulated by changing the interaction of the double-layer gratings of graphene as well as by varying various parameters of the device. Similarly, four SCMs can be excited and controlled by an oblique incident light because this light source is equivalent to two orthogonal beams of light. Furthermore, this grating can be utilized in the fabrication of mid-infrared optical devices, such as filters and refractive index sensors. This grating, with double-layer graphene arrays, has the potential to excite and manipulate the mid-infrared electromagnetic waves in future photonic integrated circuits.

Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects.

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity against PDE1C (IC50 = 10 nM), high selectivity over other PDEs except for PDE4, and weak calcium channel antagonistic activity. Administration of compound 2g exhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-ß1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2g increased the levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2g were through the regulation of cAMP and cGMP.

Discovery of novel PDE4 inhibitors targeting the M-pocket from natural mangostanin with improved safety for the treatment of Inflammatory Bowel Diseases.

Inflammatory Bowel Diseases (IBDs) are chronic disorders with iterative intestinal mucosal inflammation which remain unmet medical needs. PDE4 inhibitors were reported to be novel anti-IBD agents, but their clinical use was hampered by side effects such as emesis and nausea. Herein, structure-based discovery of natural mangostanin (1) targeting the M-pocket resulted in the novel and potent PDE4 inhibitor 22d (IC50 = 3.5 nM) and favorable physico-chemical properties. X-Ray study revealed that 22d interacted tightly with the M-pocket and maintained the key interactions between PDE4 and roflumilast. Worthy to note that compounds 22d and our previously reported 4e and 18a, originating from mangostanin, all caused no emesis on beagle dogs at the oral dose of 10 mg/kg, confirming the safety superiority of scaffold in mangostanin derivatives over that in positive roflumilast. Finally, administration of 22d (5.0 mg/kg, twice-daily) exhibited comparable anti-IBD effects to the positive control dipyridamole (25.0 mg/kg, twice-daily) in the dextran sulfate sodium (DSS)-induced IBD mice model, indicating its potential as a novel anti-IBD agent.